238 Transcriptome profiling of primary bovine macrophages from cows with Johne’s disease suggests a tolerance state induced by convergent signalling via NF-κB and its synergistic tolerized genes.
Bibliographic record
Abstract
Mycobacterium avium ssp. paratuberculosis (MAP) causes Johne’s disease (JD) in ruminants. The mechanisms of JD pathogenesis are still unclear, but it is known that this obligatory bacterium manipulates macrophages for its survival and long-term infection success in its host. A comparative transcriptomic analysis (next-generation RNA sequencing) was performed to study the global transcriptional shift mechanism observed in macrophages from JD-positive (+) cows (serum-ELISA positive for MAP antigens and excreting live MAP in their feces). Six JD-negative (−) cows and six JD(+) cows were selected. Monocyte-derived macrophages (MDM) were infected ex vivo for 1, 4, 8, and 24 h with live MAP at a multiplicity of infection of 10:1. While MAP-infected macrophages from JD(−) cows showed a robust pro-inflammatory induction of 3,765 genes (p < 0. 05) during the first 1 to 8 h (TNF, NF-κB, and cytokine members), only 31 genes were differentially expressed for JD(+). The top upregulated genes subsequently (24 h) shifted toward an anti-inflammatory and pro-resolution state. This distinct tolerization signature was confirmed in JD(+) macrophages during a subsequent exposure to MAP. Validation of key tolerized genes showed that JD(+) macrophages were shaped to not respond to subsequent transcriptional and immune MAP stimuli. For instance, while a synergistic activation of NF-κB, MAPK, and IRF pathways were associated with acute cytokine responses in JD(−), the canonical NF-κB pathway (p50/p65/BCL3) and the sequestosome were tightly regulated in JD(+) macrophages. Understanding the precise mechanism of the distinct transcriptional stimulation observed in JD(+) macrophages is paramount for eventual development of a treatment or even treatments. Our findings support the hypothesis that MAP could induce a tolerant state in the circulating monocytes of JD(+) cows, thus preventing response to a subsequent MAP exposure. This report provides important clues about MAP survival mechanisms and how MAP manipulates macrophages to promote disease persistence in dairy cattle.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".